This project aims at causing a major paradigm-shift in regenerative medicine. In the past, attempts to re-establish synaptic connectivity following injury have met great difficulties. A new work yielded evidence that mechanical force, applied either naturally or artificially at individual nascent synapses, initiates and enhances their connectivity. This FORCE (force orchestrated retrograde synaptic enhancement) mechanism is likely based on a property of cells conserved through evolution and, thus, has the potential to apply widely including regenerative medicine. In this project, we seek to establish the basis for novel strategies that make synaptic restoration possible. Genetics, bioengineering, computational bioinformatics and nanotechnology will be combined to test the hypothesis: mechanical force not only initiates and enhances but also restores neural connectivity. If successful, this project will shift the focus in regenerative medicine from moleculo-centric to mechano-centric approaches. PUBLIC HEALTH RELEVANCE: This project aims to introduce an important new concept to regenerative neuromedicine. Regeneration of central nervous system neurons after injury faces daunting challenges. We propose to explore the potential of mechanical force being an integral part of initiation, enhancement and restoration of synapses in vivo and, thereby, seek to establish a foundation for novel neural restoration strategies.